Memorandum by the Specialist Advisory
Committee on Antimicrobial Resistance (SACAR):
SURVEILLANCE, DIAGNOSTICS AND THE ROLE OF
PRESCRIBING. SOME PRIORITIES IN THE FIELD OF AMR
1. The Seventh Report of the House of Lords
Science and Technology Committee of March 1998 into resistance
to antibiotics and other antimicrobial agents made a considerable
impact in the United Kingdom and further afield. The report highlighted
the fact that resistance to these drugs was a "major threat
to public health". The report contained many recommendations,
most of which are now being set in motion by the UK Government
and other relevant academic and professional bodies. Amongst these
recommendations was the firm suggestion that an over-arching committee
to advise on problems of antimicrobial resistance and the use
of these agents in both human and animal health, as suggested
by the Swann Committee in 1969, should be set up. In July 2001
the Specialist Advisory Committee on Antimicrobial Resistance
(SACAR) under the Chairmanship of Professor Richard Wise was convened
with membership drawn from all relevant areas of the medical and
allied professions, academe and industry, with observers from
the devolved administrations of the UK. One of the first acts
of SACAR was to draw up a list of priorities and amongst these
was the realisation that surveillance of antimicrobial resistance
was absolutely fundamental. Without accurate information, not
only is it impossible to judge the extent of the problem of antimicrobial
resistance, but it will not be possible to judge the efficacy
or otherwise of any attempts that are made to control the problem
in either hospitals or the community.
2. Antibiotics revolutionised medicine during
the 20th Century, curing classical infectious diseases, safeguarding
surgery and permitting immunosuppressive procedures that previously
were unthinkable. Unfortunately, though, antibiotics exert a Darwinian
selection for resistant bacteria and there is now international
concern that the "antibiotic revolution" is under threat.
50 years ago, 95 per cent of Staphylococcus aureus isolates
were susceptible to penicillin; nowadays 95 per cent are resistant.
In many countriesincluding the UKover 30 per cent
of S. aureus isolates are now also resistant to methicillin,
which was developed to overcome staphylococcal resistance to penicillin.
Vancomycin retained universal activity against gram-positive cocci
until 1986; but now 20 per cent of Enterococcus faecium
isolates from bacteraemias in England and Wales are vancomycin
resistant, as are up to 80 per cent of E. faecium from
bloodstream infections in the USA. Third-generation cephalosporins
seemed a panacea against gram-negative bacteria in the 1980s.
Now, however, cephalosporin resistance is being reported at many
centres. Carbapenems retain activity against most cephalosporin-resistant
Enterobacteriaceae, but resistance is slowly emerging in
some important pathogens. A few hospital isolatesmostly
of non-fermentative bacteria (specifically Acinetobacter
and Pseudomonas spp.)are resistant to all reliable
antibiotics. Through the 1990s there was a dearth of new antibiotics,
let alone new antibiotic classes, being developed and, although
new antibiotics are now being developed against gram-positive
bacteria (such as MRSA and enterococci), there remains a near-total
lack of new anti-gram-negative agents.
3. Antiviral drug development is now mirroring
the speed of early development of antibacterials. Over 25 approved
antivirals are available for use against such diverse viruses
as HIV, hepatitis B and C, herpesviruses such as herpes simplex
and cytomegalovirus, and respiratory viruses such as influenza
and RSV. These drugs have had some astounding impacts on health,
such as the dramatic reductions in morbidity and mortality in
those infected with HIV. However, resistance to virtually all
available drugs has been documented. Such resistance is encoded
within the viral genome, and is associated with disease progression.
More recently, transmission of drug resistant HIV has been documented,
and appears to be increasing.
4. This document briefly addresses areas
of concern identified by SACAR in relation to surveillance for,
diagnosis of, and the role of prescribing in, antimicrobial resistance.
SACAR is aware that the Sub-Committee for Fighting Infection will
not be studying AMR as a prime area of inquiry. We have therefore
limited our evidence to three areas which SACAR believe are a
priority for development, particularly in the context of the CMOs
strategy "Getting ahead of the Curve" and the establishment
of the new Health Protection Agency.
5. Effectiveness of current surveillance
systems. The need for improved surveillance of AMR was highlighted
in the House of Lords report on this subject in 1998. Existing
mechanisms for surveillance have developed in a piecemeal way
in the UK. These need to be improved, developed and co-ordinated.
We identify areas where additional work or new investment might
be considered. We consider these at laboratory, hospital and community
levels, particularly emphasising the need to build on the backbone
of existing "passive surveillance" mechanisms, to develop
a system of sentinel surveillance based on defined populations.
5.1 There have been considerable developments
already achieved in antimicrobial resistance surveillance, particularly
through the PHLS, in line with the priorities identified in the
DoH UK Antimicrobial Resistance Strategy and Action Plan published
in June 2000. Strengthening of surveillance will presumably lie
within the future remit of the Health Protection Agency and will
require close collaboration between epidemiologists, microbiologists
and clinicians. With regard to antiviral resistance, such surveillance
is at an earlier stage of development.
5.2 Generally, better understanding is required
of the "drivers" for antibiotic resistance in hospitals
(high intensity of antibiotic use in relatively small numbers
of vulnerable/immunocompromised individuals for a range of common
and "unusual" organisms) and in the community (low intensity
use in large numbers of immunocompetent individuals) for common
The interaction between them.
Their relative contributions to emerging
population patterns of antimicrobial resistance.
5.3 Surveillance should improve this understanding
in order to achieve action to limit the emergence and spread of
5.4 Antiviral drug development is moving
apace. The principles of the emergence and transmission of antibiotic
resistance mirror many of those of antiviral resistance. We have
an opportunity to set in place appropriate laboratory, clinical
and epidemiological structures to monitor and limit spread of
these viruses, and therefore avoid the mistakes made with antibiotics.
6.1 Laboratory issues
Much surveillance of resistance depends on the
collection of routine susceptibility data from diagnostic laboratories.
These data are much less comprehensive than those available in
other developed countries. Specifically:
Isolates of Enterobacteriaceae
(the largest group of gram-negative bacteria) are often not identified
to species level in the UK, except from bacteraemias. This
is inadequate because the relative proportions of different gram-negative
pathogens are changing among hospital patients and because some
species are more prone to develop resistance than others. Thus,
observed shifts in resistance prevalence may reflect either a
shift in species prevalence or a shift in resistance prevalence
within species. These possibilities are indistinguishable if bacteria
are not identified properly.
Isolates are tested with too few
antibiotics. Most UK laboratories test circa six drugs
per isolate (the maximum number of discs that conveniently fit
on a standard nine cm petri dish). In France 16 discs would be
tested. Modern automated susceptibility testing systems test circa
18-23 drugs per isolate. If bacteria have been identified to species
level and sufficient drugs are tested, resistance mechanisms can
often be inferred from phenotypes, aiding therapeutic choice and
Isolates from different places are
tested with different antibiotics. This again reflects isolates
being tested with few antibiotics. If laboratories tested a wider
range of agents it would be possible to agree a standard core
set to be included by all sites.
Antiviral resistance data is obtained
from a few specialist laboratories at present. However, there
are already a variety of methods used, especially for HIV resistance,
with a lack of standardisation of procedures and interpretation.
Methodology. Adoption of BSAC disc method
has improved standardisation of disc testing in the UK. Nevertheless,
this improvement is compromised by lack of species identification
and by the limited ranges of antibiotics tested at most labs.
Further improvement could best be achieved by adoption of automated
testing. These provide I/D, standardisation and use wide panels
of antibiotics. Their "expert systems" filter the results,
identifying unusual profiles that deserve reference laboratory
investigation. Moves towards standardisation of antiviral resistance
assays, interpretation and reporting should be made as a matter
6.1.1 Molecular characterisation of resistance
Detailed investigation by a reference, specialist
or academic laboratory is warranted where unexpected resistances
are found at a diagnostic laboratory, eg:
Resistance in a species that was
previously always susceptible.
Resistance to unusual combinations
of analogues within a drug family.
Where resistance is increasing dramatically,
either locally or nationally.
There is a need to ensure appropriate co-operation
and co-ordination of expertise currently within NHS, PHLS and
academic institutions (especially with the changes being made
consequent on the formation of the HPA) in order to deliver such
analyses. The precise investigations vary with the particular
situation but typically include sequencing of resistance gene(s)
and identification of its location (integron, transposon, plasmid
or chromosome), also biochemical characterisation of the gene
product, which may be an antibiotic degrading enzyme, efflux system
or target modifying activity. Also vital is determination of whether
resistance is encoded by a transferable element or not. If multiple
resistant isolates are found it is important to identify whether
a single resistant strain has disseminated among patients, whether
a promiscuous resistance plasmid has transferred among strains
or whether they represent independent evolution. Application of
phylogenetic approaches to sequence based resistance testing of
viruses allows for identification of epidemiological loci of transmission
The selection of appropriate isolates for these
studies can be much-strengthened by improved reporting of routine
data. Molecular investigation of resistance itself depends on
the recruitment and retention of appropriate staff in what has
recently often been seen as an unfashionable area of molecular
6.1.2 Aside from the problems outlined as
above, existing laboratory-based surveillance includes very limited
data on the source of tested organisms or the clinical basis for
testing. Thus data cannot be related to any population denominator
(within or outside hospitals) to estimate, for example, changing
prevalence of resistance over time. Furthermore, the bacteria
that reach laboratories may be a very biased sample of circulating
organisms which further limits our understanding of true patterns
of resistance in the population. Thus clinically based sentinel
surveillance schemes are important. Where the costs of resistance
testing are large (eg HIV@ £250/test) efforts must be made
to capture routinely acquired laboratory results and full associated
clinical data within nationally based databases, since drug therapy
information is vital to understand apparent trends in resistance
6.2 Hospital surveillance
6.2.1 Improved information is required concerning
hospital prescribing (numbers, type and reason for prescribing).
At present, considerable investment is being planned for development
of Information Technology for the NHS. A national prescribing
database for hospitals (and associated IT) would be a very important
element in understanding AMR. This should be linkable on to data
on resistance patterns in hospitals (improved as above).
6.2.2 In the shorter term, we are aware
that there are commercially funded systems recording in-patient
prescribing (eg IMS, and DMD). While these systems collect data
from some NHS hospitals, we understand that these data are not
widely available to the NHS. The possibility of using IMS/DMD
databases for correlating prescribing patterns in hospitals with
antibiotic resistance patterns in sentinel hospitals should be
6.2.3 Strategies for monitoring antimicrobial
resistance in hospital should be closely co-ordinated with surveillance
activities to monitor health care associated infections and related
6.3 Community surveillance
6.3.1 Surveillance in patterns of resistance
in the community is restricted by:
The considerable bias in sampling
specimens sent for microbiological tests reaching the laboratory.
The lack of population denominators.
The limitations of PACT data on primary
care prescribing (no data on reasons for prescribing).
The difficulties in identifying the
source of specimens (hospital or community) in RGSD.
Poor understanding of the extent
to which resistance in the community is initially acquired in
hospital or outside and vice versa.
The ability to identify low frequency
events, such as the emergence of a novel resistance.
6.3.2 Existing surveillance systems in the
community require enhancement and investment in order to provide
timely information on emerging resistance and to monitor trends
in susceptibility of common bacterial infections. Linkage of microbiological
data to appropriate IT systems on prescribing is essential, to
inform the relationship between prescribing and resistance over
time. These data are needed as a source of intelligence for public
health intervention to reduce or alter inappropriate prescribing.
It is important to note that prescribing inappropriate antibiotics,
for example those unlikely to be active, is as much a problem
as general over-prescribing.
6.3.3 The absence of good denominator information
and the biases inherent in the routine specimens collected by
the laboratories indicate the need for investment in more detailed
(in-depth) surveillance to improve understanding of the drivers
and transmission dynamics of antimicrobial resistance both inside
and outside hospitals, and the interactions between them.
6.3.4 As part of its activity SACAR is considering
the need for, and design of, a national "sentinel surveillance
system" based on a defined population. Such a sentinel system
would collect a "minimum data-set" on laboratory forms
including source of specimen (GP/hospital and hospital length
of stay), reason for and site of testing and past antibiotic exposure.
It would attempt to systematically sample cases in both hospital
and community to provide adequate denominators in both settings.
Such a system would aim to identify drivers in hospital and community
and the link between the two. (An example of the establishment
of such a national "active surveillance system" is the
DoH funded Unlinked Anonymous HIV Prevalence Monitoring Programme
managed by the PHLS).
7.1 The establishment of adequate surveillance
of hospital prescribing and links to community will require appropriate
investment in information technology (see 6.2.1). A particularly
important consideration is the need for data linkage between hospital
and community, laboratory data and prescribing data.
An effective backbone of surveillance would
need the following linked data-sets:
Hospital prescribing (by clinical
Hospital antibiotic resistance (by
site and organism).
Community prescribing (by clinical
Community resistance (by site and
7.2 The increasing use of gene sequencing
to identify drug resistance associated mutations has generated
huge amounts of data, invaluable for exploring emergence of hitherto
unrecognised drug resistance patterns. With regard to HIV, for
instance, there is enormous potential in compiling UK data to
allow construction of algorithms for the direct benefit of the
NHS. New bioinformatic approaches are required to maximise such
benefit, and multi-agency collaboration is required to achieve
this. Similar datasets will be generated for other organisms.
It is essential that such "raw" data, from which laboratory
interpretation is made, is included within data storage and acquisition
for surveillance purposes, in view of the above issues and also
since this represents the molecular archaeology of circulating
microorganisms within the country as a whole.
One adverse outcome of reduced antimicrobial
prescribing might be the increase in serious sequelae of untreated
infection (eg Quinsy, community-acquired pneumonia, glomerular
nephritis, rheumatic fever) for which hospital surveillance might
be the most appropriate.
We have focused on antibiotic and antiviral
resistance but increasing use of over-the-counter antifungals
(eg fluconazole, clotrimazole) indicates the need for development
of surveillance of resistance in the medium term.